Crystal structure and Hirshfeld surface analysis of N-{N-[amino(dimethylamino)methyl]carbamimidoyl}-3-bromobenzenesulfonamide

The crystal structure of the bromobenzenesulfonamide derivative of the type 2 diabetes drug metformin is presented.


Chemical context
Metformin is a widely known effective drug for type 2 diabetes, which does not cause weight gain and rarely causes hypoglycemia. Metformin works by decreasing gluconeogenesis in the liver, increasing insulin sensitivity and preventing insulin resistance (Giannarelli et al., 2003). In addition to antidiabetics, metformin shows confirmed benefits against aging (Barzilai et al., 2016) and various diseases such as polycystic ovary syndrome (Lord et al., 2003), cancers (Libby et al., 2009), obesity (Jing et al., 2018), liver disease (Lin et al., 2000) and cardiovascular disease (Rena & Lang, 2018). In recent decades, there has been great interest in metformin because of its multiple medical applications and low toxicity. However, metformin also has some disadvantages, such as low bioavailability, incomplete absorption, and gastrointestinal side effects. Gliclazide is an oral sulfonylurea antidiabetic agent that works by stimulating insulin synthesis (Sarkar et al., 2011). We think that the combination of the two with different mechanisms of action can synergize and result in a potent hypoglycemic effect. In addition, the combination can improve their physico-chemical properties and alleviate the side effects caused by high doses of a single drug.
Introducing sulfonyl into small medical molecules is an important strategy in modifying the molecular structure of drugs. Sulfonyl can provide two hydrogen-bond acceptors, and the introduction of the sulfonyl group can improve the bioactivity of the compound by increasing the hydrogen-bond interactions between drug and target. In addition, the sulfonyl group has a relatively stable structure, and the introduction of sulfonyl can block easily metabolizable sites and prolong its time of action, improving its bioavailability, and thereby improving the pharmacokinetic properties of small molecules. In summary, it makes sense to synthesize ion pairs of gliclazide and sulfonyl-modified metformin and investigate its pharmaceutical properties. Herein we report the crystal structure and Hirshfeld surface analysis of the title compound, C 10 H 14 BrN 5 O 2 S, obtained during our efforts to crystallize the ion pair with gliclazide.

Structural commentary
The title compound crystallizes in the triclinic space group P1 with two molecules (A containing S8 and B containing S27) in the asymmetric unit ( Fig. 1). Although both molecules have an almost identical conformation, the bromophenyl part shows two orientations related by a rotation of 180 (Fig. 2). The hydrogen atoms involved in the intramolecular hydrogen bonds N11Á Á ÁN15 (molecule A) and N30Á Á ÁN34 (molecule B) are shared by the two nitrogen atoms with an occupancy of 0.85 (4) at atoms N15 and N34, and 0.15 (4) at atoms N11 and N30. The dihedral angles between the phenyl ring (C1-C6 in A, C20-C25 in B) and the best plane through the N-containing moiety (N11-C19 in A and N30-C38 in B) are 87.12 (12) and 96.05 (12) in A and B, respectively. Next to the intramolecular hydrogen bonds N15-H15BÁ Á ÁN11 and N34-H34BÁ Á ÁN30, a short interaction is present between atoms H16B and O9 in A, and H35B and O9 in B (Table 1).

Figure 1
The molecular structure of the two independent molecules (A and B) of the title compound, showing the atom labelling scheme. Displacement ellipsoids are drawn at the 30% probability level. Only the major component is shown. Intramolecular interactions are shown as dotted lines.

Figure 6
Partial crystal packing of the title compound, showing thestacking between the phenyl rings. Centroid to centroid distances are given in Å .     4 for the N-containing part of the title compound, as shown in  (Lemoine et al., 1994), YEJVOC (Jiang et al., 2022); for more details, see the supporting information]. In contrast to the title compound, all 17 compounds bear a positve charge. The histogram of the torsion angle TOR1 illustrates that the majority of these fragments are non-planar (Fig. 9b). For the title compound, this torsion angle is À177.5 (4) and À171.8 (4) in A and B, respectively.

Synthesis and crystallization
The reaction scheme to synthesize the title compound is given in Fig. 10. Metformin hydrochloride (662.5 mg, 4.0 mmol) was dissolved in 1M sodium hydroxide solution (320 ml, 8.0 mmol). The mixture was stirred for 30 min at room temperature. After the reaction was complete, water was removed under reduced pressure and the residue was dissolved in cold anhydrous methanol. The sodium chloride was filtered off and the filtrate was evaporated under reduced pressure to obtain basic metformin.
The basic metformin (258.2 mg, 2.0 mmol) and 3-bromobenzenesulfonyl chloride (144 mL, 1.0 mmol) were dissolved in 6 mL of anhydrous dichloromethane and stirred under a nitrogen atmosphere for 3 h at room temperature. The solvent was removed on a rotary evaporator and the residue was purified by column chromatography (eluent: MeOH: CH 2 Cl 2 = 1:10) to obtain the title compound as a colourless solid.
To obtain its hydrochloride salt, the title compound was dissolved in ethanol and stirred at room temperature. An ethanol solution of hydrochloric acid was added dropwise until pH = 2 and the reaction was followed by TLC. After completion of the reaction, the solvent was removed under reduced pressure to obtain the hydrochloride salt.
The hydrochloride salt (76.7 mg, 0.2 mmol) and sodium gliclazide (69.3 mg, 0.2 mmol) were dissolved in 5 mL of acetone and stirred overnight at room temperature. The solvent was removed under reduced pressure and a lightyellow solid was obtained, which was expected to be the sulfonylurea salt of the title compound.
Cuboid-shaped colourless crystals were grown in an NMR tube by slow evaporation over two weeks using deuterated chloroform as solvent. However, the grown crystals consist of the title compound and not of its sulfonylurea salt.
NMR spectra of the title compound were recorded on a 400 MHz

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. All hydrogen atoms bound to carbon were placed at idealized positions and refined using a riding model, with U iso (H) values assigned as 1.2U eq or 1.5U eq (methyl only) of the parent atoms, with C-H distances of 0.93 (aromatic) and 0.96 Å (methyl). The hydrogen atoms bound to nitrogen were located in a difference-Fourier map and

Figure 10
Reaction scheme for the synthesis of the title compound. refined freely with U iso (H) values assigned as 1.2U eq of the parent atoms. The occupancy factors of hydrogen atoms H11 and H15B (molecule A), and H30 and H34B (molecule B) involved in intramolecular hydrogen bonds converged during refinement to 0.85 (4) for H15B and H34B, and 0.15 (4) for H11 and H30.   (Rigaku OD, 2022); program(s) used to solve structure: SHELXT2014/5 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2016/4 (Sheldrick, 2015b); molecular graphics: Olex2 1.3 (Dolomanov et al., 2009); software used to prepare material for publication: Olex2 1.3 (Dolomanov et al., 2009). Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.